4-amino-2-phenyl-6-thiopyrimidines



United States Patent 3,498,984 4-AMINO-2-PHENYL-6-THIOPYRIMIDINES ArthurA. Santilli, Havertown, and Doug H. Kim, Strafford, Pa., assignors toAmerican Home Products Corwherein R R and R are defined as above. Thecyclization reaction between the commercially available diethyl malonateand an appropriate benzamidine is effected by refluxing a substantiallyequimolar mixture of these poration, New York, N.Y., a corporation ofDelaware 5 reactants in a reaction-inert solvent, such as ethanol, in NoDrawing. Filed Oct. 28, 1966, Ser. No. 590,198 the presence of sodiummetal for a period of about two C C0711 51 51/44 to about five hours.After the reaction is complete, the (1260-4555 9 Claims reaction mixtureis filtered, the filter cake dissolved in water and precipitated byacidification to afford a 2- l 10 phenyl-4,6-(lH,5H)-pyrimidinedione(1). ABSTRACT OF THE DISCLOSURE 5 The above prepared2-phenyl-4,6(1H,5H)-pyrimidine- 4-amino-2-phenyl-6-thiopyrimidines havebeen snythedione (I) is then admixed with phosphoryl chlorideand sizedand have been found to possess anti-viral, anticon slowly combined withN,N-diethylaniline. The reaction vulsant, antibacterial, hypotensive andanti-inflammatory mixture is then heated to about reflux temperaturesfor i i a period of about three hours. Thereafter, the resulting4,6-dich1oro-2-phenylpyrirnidine (II) is separated by con- Thisinvention relates to new and noval pyrimidine ventional recoveryprocedures, e.g. concentration and recompounds In particular, thepresent invention is com crystallization from a suitable solvent, suchas ethanol. cerned with 4-amino-2-phenyl--thiopyrimidine com- Tfiechbmemmatm of a a pyrimidine (II) is performed by admixing a4,6-d1chloropounds havmg pharmacodynamrc activity.

The novel compound which are included Within the wlth *"P and heatmg theresult scope of this invention are represented by the following mg i thereactlon 3 the formula: resulting 4-am1no-o-chloro-Z-phenylpyrumdme(III) is obtamed by conventional separation methods, such as, ad- 2mixture with Water and recrystallization of the resulting N precipitatefrom an appropriate solvent, e.g. an alkanol, R

W an alkane, benzene-petroleum ether mixtures and benzene. b The4-amino-2-phenyl-6-thiopyrimidines (IV) of this invention are thenprepared by the dechlorosulfonation l of an appropriate4-amino-6-chloro-2-phenylpyrimidine (III). This reaction is effected byadmixing a 4-amino-6- wherein 1 is selected from the group Consisting ofchloro-Z-phenylpyrimidine (III) with an excess amount drogen, dichlofo,halogen, lower alkyl and lower Y; of benzylmercaptan or thiophenol for aperiod of about 2 is selected from the group Consisting of amino, H10!-fifteen minutes to about five hours at about 160 C. orPholinoethylamino, mofpholinopwpylamino, at refluex temperatures. Whenthe reaction is complete, y p p methoxyethylamino, yp py the reactionmixture is basified by the addition of an amino, 4-hydroxye hyliperazino, hydroxy (1 wer) 1ky alkali metal hydroxide and the4-amino-2-phenyl-6-thioamino, lower alkoXycarbonylmethylamino, lowerpyrimidine (IV) separated by routine procedures, e.g.kanoylarninoflower)alkylamino, hexahydroazepinyl, dicrystallization,filtration and recrystallization from asuitalkylaminoflo'wel')alkylamino, d (1 r) k y- 40 able organic solvent,e.g. cyclohexane, n-heptane, beneethylamino, and lower alkylamino; andR3 is selected Zeno-petroleum ether, ethanol, methanol, ethanol-hepfromthe group consisting of phenyl, halophenyl, lower tane, nddimethylformamide alkylphenyl, lower alkoxyphenyl, benzyl, halobenzyl,Many of the benzamidines, the 2-phenyl-4,6-(1H,5H)- lower alkylbenzyland lower alkoxybenzyl. pyrimidinediones (I),4,6-dichloro-2-phenylpyrimidines Specific examples of such compoundsinclude: 4-(4- (II), and the 6-amino-4-chloro-2-phenylpyrimidines (HI)methyl-l-piperazinyl) 2-phenyl-6-phenylthiopyrimidine; utilized in thesynthesis of the compounds of the present 4-amino-6-(4-chlorophenylthio)2-pheny1pyrimidine; 4- invention are known compounds. Others which havenot (4-chlorophenylthio) 6 [2-(morpholinoethyl)amino]-2- reviously beenknown are prepared in accord with the phenylpyrimidine and 4(4-chlorophenylthio) 6-(2- aforesaid reaction sequence, specificillustration thereof is methoxyethylamino)-2-(4-tolyl)-pyrimidine.hereinafter given in the Examples.

The novel compounds of the present invention may be In accord with thepresent invention, the new 4-aminoprepared as illustrated in thefollowing reaction scheme: 2-phenyl-6-thiopyrimidines (IV) hereindescribed have H C2H5O2C H-N R1 I R1 2 Cyohzation O NQ 02115029 HzI Q' gl Desoxychlorination Dechlorosulionatiou been found to possessinteresting pharmaceutical properties which render them useful assynthetic medicinals. More particularly, these compounds, in standardpharmacological tests, have exhibited utility as antiviral, inparticular, herpes simplex, Columbia SK polio influenza NWS;anticonvulsant; antibacterial; hypotensive and antiinflammatory agents.

When the compounds of this invention are employed as antiviral, inparticular, herpes simplex, Columbia SK polio, influenza NWS;anticonvulsant; antibacterial; hypotensive and antiinflammatory agents,they may be administered alone or in combination with pharmaceuticallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch ex-cipients as starch, milk sugar, certain types of clay and soforth. They may be administered sublingually in the form of troches orlozenges in which the active ingredient is mixed with sugar and cornsyrups, flavoring agents and dyes; and then dehydrated sufficiently tomake it suitable for pressing into a solid form. They may beadministered orally in the form of solutions which may contain coloringand flavoring agents or they may be injected parenterally, that isintramuscularly, intravenously or subcutaneously. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary wih the particular subject under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about 1 mg. to about 400 mg. per day,although as aforementioned variations will occur. However, a dosagelevel that is in the range of from about 50 mg. to about 150 mg. per dayis most desirably employed in order to achieve effective results.

The following examples are given by way of illustration.

EXAMPLE I To a stirred solution of 35.8 g. of sodium metal in one literof absolute ethanol, there is added 88.5 g. of m-toluamidinehydrochloride followed by the dropwise addition of 91.5 g. of diethylmalonate over a fifteen minute period. The reaction mixture is heatedunder reflux for four hours. The solution is filtered and the filtercake dissolved in water. The ethanol filtrate is evaporated to drynessand the solid residue added to the water solution. Upon acidification ofthe aqueous solution to pH with concentrated hydrochloric acid, a solidseparates which is removed by filtration. After washing this materialseveral times with water, the product is recrystallized from aque ousN,N-dimethylformamide to afford 2-(3-tolyl)-4,6-(lH,5H)-pyrimidinedione, M.P. 247.5 C.

Analysis.Calcd for C H N O (percent): C, 65.33; H, 4.98; N, 13.86. Found(percent): C, 65.26; H, 5.18; N, 13.68.

To a mixture of 108 g. of the above prepared 2-(3-tolyl)-4,6-(lH,5H)-pyrirnidinedione in 700 ml. of phosphoiyl chloridethere is slowly added 80g. of N,N-diethyl- .4 aniline. The reactionmixture is heated with stirring under reflux for three hours, thenevaporated to dryness in vacuo on a rotary evaporator, and ice is addedto the residual oil. The dark brown solid which results isrecrystallized from ethanol affording 82.3 g. of product, M.P. 76-78 C.,which when recrystallized from ethanol yields4,6-dichloro-2-(3-tolyl)-pyrimidine, M.P. 80-81 C.

Analysis.-Calcd for C H Cl N (percent): C, 55.24; H, 3.37; N, 11.72; Cl,29.6. Found (percent): C, 55.24; H, 3.62; N, 11.57; Cl, 29.4.

Similarly, reacting p-toluamidine hydrochloride with diethyl malonateaffords 2-(4-tolyl)-4,6-(1H,5H-pyrimidinedione which is then reactedwith phosphoryl chloride to produce 4,6-dichloro-2-(4-tolyl)-pyrimidine,M.P. 84- 85 C.

Arralysis.Calcd for C H Cl N (percent): C, 55.24; H, 3.37; N, 11.72; Cl,29.6. Found (percent): C, 55.29; H, 3.51; N, 11.44; Cl, 29.6.

EXAMPLE II To a stirred solution of 56.4 g. of sodium metal in one literof absolute ethanol there is added 156 g. of m-chlorobenzamidinehydrochloride followed by the dropwise addition of 144 g. of diethylmalonate over a fifteen minutes period. The reaction mixture is heatedunder reflux for three hours. The solution is filtered and the filtercake dissolved in water. The ethanol filtrate is evaporated to drynessand the solid residue added to the water solution. Upon acidification ofthe aqueous solution to pH with concentrated hydrochloric acid, a solidseparates which is removed by filtration. After washing this materialseveral times with water the product (123 g., M.P. 254- 256 C.) isrecrystallized from aqueous, N,N-dirnethylformamide to yield2-(3-chlorophenyl)-4,6-(1H,5H)- pyrimidinedione, M.P. 256-257 C.

AnaZysz's.-Calcd for C H N O C1 (percent): C, 53.95; H, 3.17; N, 12.59;Cl, 15.93. Found (percent): C, 53.88; H, 3.18; N, 12.57; Cl, 15.65.

To a mixture of the above prepared 2-(3-chlorophenyl)-4,6-(lH,5H)-pyrimidinedione (120.9 g.) in 500 ml. of phosphoryl chloridethere is added slowly 161 g. of N,N- diethylaniline. The reactionmixture is evaporated to dryness in vacuo on a rotary evaporator and iceis added to the residual oil. The dark brown solid which results isrecrystallized from ethanol affording 4,6-dichloro-2-(3-chlorophenyl)-pyrimidine, M.P. 118119.5 C.

Analysis.-Calcd for C H N Cl (percent): C, 46.28; H, 1.94; N, 10.8; C1,40.98. Found (percent): C, 46.30; H, 2.15; N, 10.8; C1, 40.8.

In a similar manner, reacting p-bromobenzamidine hydrobromide withdiethyl malonate produces 2-(4-bromophenyl)-4,6-(1H,5H)-pyrimidinedione,which is reacted with phosphoryl chloride to afford 2-(4bromophenyl)-4,6-dichloropyrimidine.

EXAMPLE III Employing the procedure of Example II to react 97.6 g. ofp-methoxybenzamidine hydrochloride and 92.4 g. of diethyl malonate in1500 ml. of absolute ethanol, in the presence of 36.2 g. of sodiummetal, there is produced 2- (4-methoxyphenyl) -4,6- 1H,5H-pyrimidinedione, M.P. 299-300" C. (dec.).

Analysis.Calcd for C H N O (percent): C, 60.54; H, 4.62; N, 12.84. Found(percent): C, 60.83; H, 4.98; N, 12.95.

In a similar manner, the interaction of 73.1 g. of o-toluamidinehydrochloride with 75.5 g. of diethyl malonate in one liter of absoluteethanol containing 29.6 g. of sodium affords 2 (2tolyl)-4,6-(1H,5H)-pyrimidinedione, M.P. 319-320 C.

Analysis.--Calcd for C I-I N O (percent): C, 65.33; H, 4.98; N, 13.86.Found (percent): C, 65.53; H, 5.22; N, 13.58.

A mixture of 66.5 g. of the above prepared 2-(2-tolyl)4,6-(1H,5H)-pyrimidinedione in 400 ml. of phosphoryl chloride is reactedwith 49.2 g. of N,N-diethylaniline. Recrystallization of the productfrom ethanol afiords 58.4 g. of 4,6-dichloro-2-(2-tolyl)-pyrimidine,M.P. 76.5- 77 C.

EXAMPLE IV 3,4-dichlorophenylamidine' hydrochloride (22.5 g.) is addedwith stirring to a solution of sodium (6.9 g.) in absolute ethanol (120ml.) followed by the dropwise addition of diethyl malonate (22.2 g.)over a thirty minutes period. The reaction mixture is heated underreflux for three hours and then filtered. The filter cake is dissolvedin water. The ethanol filtrate is evaporated to dryness and the solidresidue added to the water solution. Upon acidification of the aqueoussolution to p11 with concentrated hydrochloric acid, a solidprecipitates which is removed by filtration. After washing this materialwith water the product (21.5 g., M.P. 310315 C.) is recrystallized fromN,N-dimethylformamide to afiord 2-(3,4-dichlorophenyl) 4,6(lH,5H)-pyrimidinedione, M.P. 315-317" C. (dec.).

A mixture of 19.45 g. of the above prepared 2-(3,4-dichlorophenyl)-4,6-(lH,5H)-pyrimidinedione in 70' ml. of phosphorylchloride there is added 11.3 g. of N,N-di ethylaniline as in Example I.Recrystallization of the product from n-heptane afiords 19.8 g. of4,6-dichloro- 2-(3,4-dichlorophenyl)-pyrirnidine, 122-124 C.

Analysis.For C H N Cl Calcd.: C, 40.85%; H, 1.37%; N, 9.53%; Cl, 48.24%.Found: C, 41.02%; H, 1.38%; H, 9.82%; CI, 48.2%.

EXAMPLE V To a stirred solution of 56.4 g. of sodium metal in one literof absolute ethanol there is added 156 g. of p-chlorobenzamidinehydrochloride followed by the drop- Wise addition of 144 g. of diethylmalonate over a thirty minutes period. The reaction mixture is heatedunder reflux for five hours. The solution is filtered and the filtercake is dissolved in water. The ethanol filtrate is evaporated todryness and the solid residue added to the water solution. Uponacidification of the aqueous solution to pH with concentratedhydrochloric acid, a solid precipitates which is removed by filtration.Washing this material several times with water affords2-(4-chlorophenyl) -4,6-( 1H,5H) -pyrimidinedione.

To a mixture of 127 g. of the above prepared 2-(4-chlorophenyl)-4,6-(1H,5H)-pyrimidinedione in 700 ml. of phosphorylchloride there is added slowly 171 g. of N,N-diethylaniline. Thereaction mixture is heated with stirring under reflux for three hours.The reaction mixture is evaporated to dryness in vacuo on a rotaryevaporator and ice is added to the residual oil. The dark brown solidwhich results is recrystallized from ethanol afiording 82.4 g. of4,6-dichloro-2-(4-chlorophenyl)- pyrimidine, M.P. 120 121 C.

EXAMPLE VI Repeating the procedure of Examples I to IV to react anappropriate amidine with diethyl malonate, the followingpyrimidinediones are obtained which are then reacted with phosphorylchloride to form the hereinafter listed dichloropyrimidines:

4,6-dichloro il-phenylpyrimidine. pyrimidinedione.

6 EXAMPLE v11 Six grams of 4,6-dichloro-2-phenylpyrimidine is added insmall portions to 25 ml. of N-(B-aminoethyD-morpholine with slightwarming and stirring. An exothermic reaction takes place during theaddition. The resulting mixture is heated on a steam bath for severalminutes and then poured into 500 ml. of water. The semisolid productthus obtained is recrystallized from benzene and petroleum ether usingdeclorizing charcoal to give 5.0 g. of4-chloro-6-[2-(morpholino)ethylamino]-2-phenylpyrimidine, M.P. -82 C.

Analysis.For C H N OCl. Calcd.: C, 60.28%; H, 6.01%; N, 17.58%. Found:C, 60.36%; H, 6.03%; N 17.87%.

A well blended mixture of 2.7 g. of the above prepared 4-chloro-6- [2-(morpholino ethylamino] -2-phenylpyrimidine and 6.3 g. ofp-chlorothiophenol is heated in an oil bath maintaining the temperatureat 160 C. for three hours. After being cooled to room temperature, thereaction mixture is triturated with 60 ml. of 30% sodium hydroxide. Theproduct is collected on a sintered glass funnel and washed with waterrepeatedly to yield 3.7 g. of product. Upon recrystallization fromethanol, there is obtained4-(4-chlorophenylthio)-6-[2-(morpholin0ethyl)amino]-2-phenylpyrimidine,M.P. l7ll73 C.

Analysis.For C H N SOCL Calcd.: C, 61.89%; H, 5.40%; N, 13.12%; S,7.51%; Cl, 8.30%. Found: C, 61.73%; H, 5.36%; N, 13.39%; S, 7.7%; Cl,8.3.

Similiraly, 2 (4-bromophenyl)-4,6-dichloropyrimidine is reacted withN-(3-aminopropyl)-morpholine to afford 2- 4-bromophenyl) -4-chloro-6- 3-(morpholino -propropylamino]-pyrimidine which is then reacted withpchlorothiophenol to produce 2-(4-bromophenyl)-4-(4 chlorophenylthio) 6[3-(morpholinopropyl)amino]-pyrimidine.

EXAMPLE VIII Two grams of 4,6-dichloro-Z-phenylpyrimidine is added insmall portions to 10' ml. of N-methylpiperazine with slight warming andstirring. The resulting mixture is heated on a steam bath for severalminutes, then poured into 250 ml. of water. The product (2.4 g., M.P.81-87 C.) is then recrystallized from n-pentane to afford4-chloro-6-(4-methy1-1-piperazinyl)-2 phenylpyrirnidine, M.P. 9l92.5 C.

Analysis.For C15H17N4C1. Calcd.: C, 62.38%; H, 5.93%; N, 19.40%; Cl,12.28%, Found: C, 62.32%; H, 5.65%; N, 19.62%; Cl, 12.1%.

A mixture of 3.0 g. of the above prepared 4-chloro- 6-(4-methyl 1piperazinyl)-2-phenylpyrimidine and 10 ml. of thiophenol is heated underreflux for three hours and then poured into 300 ml. of water, Thereaction mixture is basified with 40% sodium hydroxide solution. Theproduct which is deposited crystallizes on cooling to afford 3.5 g. ofproduct. Recrystallization from n-heptane affords4-(4-methyl-1-piperazinyl)-2-phenyl 6 phenylthiopyrimidine, M.P. -128 C.

Analysis.-For C H N S. Calcd.: C, 69.58%; H, 6.12%; N, 15.46%; S, 8.85%.Found: C, 69.49%; H, 6.13%; N, 15.42%; S, 8.6%,

Similarly, 4-(4-ethyl-1-piperazinyl)-2-phenyl-6-phenylthiopyrimidine isproduced.

EXAMPLE IX 7 5.35%; N, 15.93%. Found: C, 59.32%; H, 5.31%; N, 15.72%.

A well blended mixture of 4.3 g. of 4-chloro-6-(2-methoxyethylamino)-2-phenylpyrimidine and 10.0 g. of p-chlorothiophenolis heated in an oil bath maintaining the temperature at 160 C. for threehours. After being cooled to room temperature, the reaction mixture istriturated with 60 ml. of 30% sodium hydroxide. The product is collectedon a sintered glass funnel and washed with water repeatedly, Tworecrystallizations of the crude product affords 2.0 g, of4-(4-chlorophenylthio)-6-[(2- methoxyethyl)amino] 2 phenylpyrimidine,M.P. 128- 130 C.

Analysis.For C19H18N3SOC1. Calcd.l C, H, 4.88%; N, 11.30%; S, 8.62%; Cl,9.54%. Found: C, 61.10%; H, 4.81%; N, 11.59%; S, 8.9%; Cl, 9.75%.

In the same manner, 4,6-dichloro-2-penylpyrimidine is reacted with3-methoxypropylamine to produce 4-chloro-6-(3-methoxypropylamino)-2-phenylpyrimidi11e, which is then reacted withp-chlorothiophenol to aflord 4-(4- chlorophenylthio) 6-- [(3methoxypropyl)amino]-2- phenylpyrimidine.

EXAMPLE X N-hydroxyethylpiperazine (7.81 g.) diluted with 20 ml. ofabsolute ethanol is added to a slurry obtained by adding 6.75 g, of4,6-dichloro-2-phenylpyrimidine to 25 ml. of absolute ethanol. Theresulting mixture is refluxed for fifteen minutes, then poured into 850ml. of water. A gummy material which separates solidifies on standingovernight. The crude product weighs 7.8 g. which is recrystallized fromn-heptane to afford4-(4-chloro-2-phenylpyrimidin-6-yl)-1-piperazineethanol, M.P. 103-105"C.

Analysis-For C H N OCl. Calcd.: C, 60.28%; H, 6.01%; N, 17.58%. Found:C, 60.08%; H, 5.70%; N, 17.48%.

A well blended mixture of 3.8 g, of 4-(4-chlor0-2-phenylpyrimidin-6-yl)-1-piperazineethanol and 7.0 g. ofp-chlorothiophenol is heated in an oil bath maintaining the temperatureat 160 C. for three hours. After being cooled to room temperature, thereaction mixture is triturated with 60 ml. of 30% sodium hydroxide. Theproduct is collected on a sintered glass funnel and washed with waterrepeatedly. Upon recrystallization from 65% ethanol, there is obtained4-[4-(4-chlorophenylthio)-2- phenyl6-pyrimidinyl]-l-piperazine ethanol,M.P. 118- 120 C.

Analysis.--For C H N SOCL Calcd.: C, 61.89%; H, 5.43%; N, 13.12%; S,7.51%; Cl, 8.31%. Found: C, 61.80%; H, 4.95%; N, 12.76%; S, 7.5%; Cl,8.29%.

EXAMPLE XI To a solution of 1.2 g. of sodium in 50 ml. of ethanol, thereis added 8.4 g. of ethyl glycinate hydrochloride and 6.7 g. of4,6-dichloro-2-phenylpyrirnidine. The reaction mixture is heated withstirring for two hours under reflux then taken to dryness on a rotaryevaporator. After the addition of 200 ml. of water the residue which isdeposited amounts to 8.5 g., M.P. 83-132 C. Recrystallization frombenzene yields 8.3 g. of N-(6-chloro-2-phenyl-4-pyrimidinyl)-glycine,ethyl ester, M.P. 147149 C.

Analysis.-For C H N O Cl. Calcd.: C, 57.64%; H, 4.84%; N, 14.40%; Cl,12.15%. Found: C, 57.66%; H, 4.85%; N, 14.59%; C1, 12.2%.

A mixture of the above preparedN-(6-chloro-2-phenyl-4-pyrimidinyl)-glycine, ethyl ester is reacted withthiophenol, as in Example X, to aifordN-(2-phenyl-6-phenylthio-4-pyrimidinyl)-glycine, ethyl ester.

In a similar manner, N-[2-(4-chlorophenyl)-6-phenylthio-4-pyrimidinyl]glycine, propyl ester and N-(2-phen yl6-phenylthio 4pyrimidinyl)glycine, ethyl ester are prepared.

EXAMPLE XII Six grams of 4,6dichloro-Z-penylpyrimidine is added in smallportions to ml. of hexamethyleneimine with slight warming and stirring.The resulting mixture is heated on a steam bath for several minutes,then poured into 500 ml. of water. The product (7.56 g., 6264 C.) thusobtained is recrystallized from n-heptane affords 4- chloro 6(hexahydroazepin-l-yl)-2-phenylpyrimidine, M.P. 6466 C.

Analysis.For C H N Cl. Calcd.: C, 66.77%; H, 6.30%; N, 14.60%, Found: C,66.80%; H, 6.37%; N, 14.26%.

A mixture of the above prepared4-chloro-6-(hexahydroazepin-l-yl)-2-phenylpyrimidine is reacted withpchlorothiophenol, as in Example X, to produce 4-(4- chlorophenylthio) 6(hexahydroazepin-l-yl)-2-phenylpyrimidine.

EXAMPLE XII-I Employing the procedure of Example VII, 7.0 g. of 4,6-dichloro-Z-(p-chlorophenyl)-pyrimidine and 30 ml. of N-(fl-aminoethyl)-morpholine is reacted to produce 8.9 g. of product.Recrystallization from n-heptane afiords 4- chloro-2-(4 chlorophenyl) 6[2-(morpholino)ethylaminol-pyrimidine, M.P. 127129 C.

Analysis.For C H N Cl Calcd.: C, 54.40%; H, 5.14%; N, 15.86%; Cl,20.07%. Found: C, 54.50%; H, 4.89%; N, 16.08; Cl, 19.70%.

Reacting 6.0 g. of 4-chloro-2-(4-chlorophenyl)-6-[2-(morpholino)ethylamino]-pyrimidine with 14.0 g. of pchlorothiophenolyields 4.3 g. of product. Two recrystallizations from absolute ethanolafford 2-(4-chlorophenyl)- 4- (4 chlorophenylthio -6-[2- (morpholinoethylamino} pyrimidine, M.P. l59l6l C.

AnanlysiS.F0r C H N SOCl Calcd.: C, 57.26%; H, 4.81%; N, 12.14%; S,6.95%; Cl, 15.37%. Found: C, 57.23%; H, 4.64%; N, 12.27%; S, 7.0%; Cl,15.3%.

Similarly, 4 chloro2-(4-ch1orophenyl)-6-[3-(morpholino)prpoylamino]-pyrimidine is reactedwith p-ethyl thiophenol to produce 2(4-chlorophenyl)-4-(4-ethylphenylthio -6- 3- (morpholino)propylamino1-pyrimidine.

EXAMPLE XIV Seven grams of 4,6 dichloro-2-(p-chlorophenyl)-py rimidineis added in small portions to 30 ml. of ii-methoxyethylamine with slightwarming and stirring. The resulting mixture is heated on a steam bathfor several minutes, then poured into 500 ml. of water. The product thusobtained is recrystallized from n-heptane to give 5.6 g. of 4chloro-2-(4-chlorophenyl)-6-[2-(methoxyethyl)- amino1-pyrimidine, M.P.64-65" C.

Analysis.-For C13H13N3OC1. Calci: C, H, 4.39%; N, 14.09%. Found: C,52.42%; H, 4.56%; N, 13.75%.

A well blended mixture of7.0 g. of the above prepared pyrimidine and16.3 g. of p-chlorothiophenol is heated in an oil bath maintaining thetemperature at 160 C. for three hours. After being cooled to roomtemperature, the reaction mixture is triturated with 60 ml. of 30%sodium hydroxide. The product is collected on a sintered glass funneland washed with water repeatedly. Two recrystallizations from n-heptaneafford 3.0 g. of 2-(4-chlorophenyl) 4(4-chlorophenylthio)-6-[(2-methoxyethyl)- amino]-pyrimidine, M.P.135-138 C.

AIZHIYSI Sr-JFOT C19H17N3SOC12. Calcd.: C, H, 4.22%; N, 10.34%; S,7.89%; Cl, 17.45%. Found: C, 56.21%; H, 4.13%; N, 10.6%; S, 7.9%; Cl,17.3%.

Similarly, 4,6-dichloro-2-(3-chlorophenyl)-pyrimidine is reacted withB-methoxyethylamine to produce 4-chloro- 2 (3 chlorophenyl)- 6-[2-(methoxyethyl)amino]-pyrimidine (M.P. 76 C.) which is then reactedwith pfluorothiophenol to afford2-(3-chlorophenyl)-4-(4-fluorophenylthio -6-[ (Z-methoxyethyl) amino-pyrimidine.

EXAMPLE XV Two grams of 4,6-dichloro-Z-phenylpyrimidine is added insmall portions to 10 ml. of N-methylpiperazine with slight warming andstirring. An exothermic reaction takes place during the addition. Theresulting mixture is heated on a steam bath for several minutes and thenpoured into 250 ml. of water. The product thus obtained isrecrystallized from n-pentane to afford 4-chloro-6(4-methyl-1-piperazinyl)-2-phenylpyrimidine, M.P. 9192.5 C.

A well blended mixture of the above prepared 4-chloro- 6(4-methyl-1-piperazinyl)-2-phenylpyrimidine (2.0 g.) and 5.0 g. ofp-chlorothiophenol is heated in an oil bath maintaining the temperatureat 160 C. for three hours. After being cooled to room temperature, thereaction mixture is triturated with 60 ml. of 30% sodium hydroxide. Theproduct is collected on a sintered glass funnel and washed with waterrepeatedly. It amounted to 2.9 g. and melted at 145150 C. Uponrecrystallization from absolute ethanol, there is obtained4-(4-ch1orophenylthio)- 6-(4 methyl l-piperazinyl)-2-pheny1pyrimidine,M.P. 152154 C.

Analysis.For C H N SCl. Calcd.: C, 63.54%; H, 5.33%; N, 14.12%; S,8.08%. Found: C, 63.78%; H 5.60%; N, 14.07%; S, 8.1%.

In a similar manner, the following intermediates are prepared which arethen reacted with an appropriate thiophenol to afford the hereinafterlisted products:

Intermediates Products 6-eh1oro-2-(3-chloropheny1)-4-[2-(dimethylamino)ethylamino]- pyrimidine, M.P. 77-78.5 C.

2-[4chloro2-(4-methoxyphenyl)-6- pyrimidinylamino]ethanol, M.P. 133134.5C.

4-[4-chloro 2-(i-methoxyphenyl)- pyrimidin-fi-yH-l-piperazineethanol,M.P. 113-114 C.

4-ehl0ro-642-(dimethylamino) ethylamino]-2-(4-tolyl)-pyrim1- dine, M.P.6466.5 C.

6-chloro-2-(-fiuorophenyl) -4-[4- (dimethylamine) butylamino]-pyrimidine.

3-[4-ch1oro-2-(4-methoxyphenyD-6- pyrimidinylamino1-propanol.

2-(3-chloropheuyD-4-(t-chlorophenylthio)-6-[(2-dimethylamino)ethylamino]-pyrimidine,M.P. 108109.5 C. 2-[2-(4-methoxyphenyl)-4-pheny1-thio-6-pyrimidinylamino]- ethanol. 4-[4-(4-chlorophenylthio) -2-(4-methoxyphenyl)-pyrimidin6- y1]-1-piperazineethano1.4-(4ehlorophenylthio)45-[2- (dimethylamino)ethylamino]-2- (4-tolyl)-pyrimidine, M.P 1385-1385 C. 2-(4-fiuorophenyl) -6-[4-dimethy1-amino)buty1amino14-(4-toly1- thio)-py'rirnidine. 3-[2-(4-methoxyphenyl)-4-phenylthio-6-pyrimidinylamino]propanel.

EXAMPLE XVI The above prepared pyrimidine is reacted withp-chlorothiophenol to obtain a product which is repeatedlyrecrystallized from cyclohexane to afford 4-(4-chlorophenylthio) -2-( 3,4-dichlorophenyl) -6- 2- (dimethylamino ethylamino1-pyrimidine-Vzcyclohexane, MJP. 99'103 C.

Analysis.For C H Cl N S- /2 cyclohexane. Calcd.: C, 55.70%; H, 5.08%; N,11.30%; S, 6.47%; Cl, 21.45%. Found: C, 55.47%; H, 4.92%; N, 11.53%; S,6.5%; Cl, 21.8%.

Similarly, 7.0 g. of 4,6-dichloro-2-(p-chlorophenyl)-pyrimidine and 30ml. of N,N-dimethy1-ethylenediamine are reacted followed by reaction ofthe crude product with g. of p-chlorothiophenol. The product (8.0 g.) isrecrystallized from heptane and then from absolute ethanol to afford2-(4-chlorophenyl)-6-(4-chlorophenylthio)-4-[2dimethylaminoethyl)amino]-pyrimidine, M.P. 98-100 C.

Analysis.FOr C H N 'SCl Calcd.: C, H, 4.81%; N, 13.36%; S, 7.65%. Found:C, 57.46%; H, 4.76%; N, 13.62%; S, 7.7%.

10 EXAMPLE XVII A solution of 7.2 g. of4,6-dichl0ro-2-(p-tolyl)-pyrimidine and 7.8 g. ofN-hydroxyethylpiperazine in 35 ml. of absolute ethanol is refluxed forfifteen minutes. Pouring of the resulting solution into 700 ml. of watercauses separation of a gummy material which solidifies on standing. Thecrude product weighs 8.7 g. and recrystallization from n-heptane affords4-[4-chloro-2-(4-tolyl) 6 yrimidinyl]-1-piperazine ethanol, M.P.103.5104.5 C.

Analysis.For C H N OCl. Calcd.: C, 61.34%; H, 6.36%; N, 16.83%; Cl,10.65%. Found: C, 61.17%; H, 6.07%; N, 17.07%; Cl, 10.7%.

A well blended mixture of 4.3 g. of the above prepared compound and 9.0g. of p-chlorothiophenol is heated in an oil bath maintaining thetemperature at C. for one half hour. After being cooled to roomtemperature, the reaction mixture is triturated with 60 m. of 30% sodiumhydroxide. The product is collected on a sintered glass funnel andwashed with water repeatedly. In this manner, is obtained 4- 4-4-chlorophenylthio -2- 4-tolyl) -pyrimidin- 6-yl]-1-piperazineethanol,M.P. 123-125 C.

Analysis.-For C H N SOCl. Calcd.: C, 62.64%; H, 5.71%; N, 12.71%; S,7.27%; Cl, 80.4%. Found: C, 62.57%; H, 5.90%; N, 12.83; S, 7.3%; Cl,8.04%.

Similarly, 4-[4-(4-brornophenylthio) 2 (4propylphenyl)-pyrimdin-6-yl]-1-piperazineethano1 is synthesized.

EXAMPLE XVIII A solution of 7.2 g. of4,6-dichloro-2-(p-toly1)-pyrimidine and 4.5 g. of fl-methoxyethylaminein 35 ml. of absolute ethanol is refluxed for fifteen minutes. Pouringof the resulting solution into 700 ml. of water causes separation of agummy material which solidifies on standing. The crude product weighs7.3 g. and recrystallization from n-heptane affords4-chloro-6-[2-(methoxy)ethylamino]-2- (4-to1yl) pyrimidine, 7072 C.

Analysis.-For C H N OCl. Calcd.: C, 60.54%; H, 5.81%; N, 15.13%; Cl,12.61%. Found: C, 60.41%; H, 5.86%; N, 15.27%; Cl, 13.0%.

A mixture of 4.3 g. of the above prepared compound and 7.0 g. ofp-chlorothiophenol is heated in an oil bath maintaining the temperatureat 160 C. for three hours. After being cooled to room temperature, thereaction mixture is triturated with 60 ml. of 30% sodium hydroxide. Theproduct is collected on a sintered glass funnel and washed with waterrepeatedly. Recrystallization of the crude product (6.7 g.) from aqueousethanol affords 4-(4- chlorophenylthio)-6-(2-methoxyethylamino)-2-(4tolyl) pyrimidine, M.P. 141144 C.

Analysis.For C H N SOC1. Calcd.: C, 62.24%; H, 5.22%; N, 10.89%; S,8.31%; Cl, 9.19%. Found: C, 62.08%; H, 5.20%; N, 11.01%; S, 8.34%; Cl,9.62%.

In a similar manner, 4,6-dichloro-2-(p-ethylphenyl)pyrimidine is reactedwith 'y-methoxypropylamine to obtain 4- chloro-2-(4-ethylphenyl)-6-[3(methoxy)propylamino]- pyrimidine which is then reacted with thiophenolto afford 2-(4-ethylphenyl) -6- (3 -methoxypropylamino -4phenylthiopyrimidine.

EXAMPLE XIX In the above manner, the following products are obtained:

4- (4-chlorophenylthio) -2- 4-methoxyphenyl) -6-[(Z-dimethylamino)ethylamino]-pyrimidine, M.P. 121-122. C.;

2-(4-chlorophenyl)-4-(4-ehl0rophenylthio)-6-[2(diethylamino)ethylaminoJ-pyrimidine, M.P. 112-l14 C.;

N-[2-(6-[4-chlorophenylthio]-2-phenylpyrimidin-4 ylamino)ethyl]-acetamide, M.P. 165-166 C.; and

2-(4-chlorop'henyl)-4-(4 chlorophenylthio) 6 (4-methylpiperazin-l-yl)pyrimidine, MJP. 163-165 C.

EXAMPLE XX A solution of 7.8 g. of 4,6-dichloro-2- (m-chlorophenyl)-pyrimidine and 6.0 g. of N-methylpiperazine in 35 ml. of absoluteethanol is refluxed for fifteen minutes. Pouring of the resultingsolution into 700 ml. of water causes separation of a gummy materialwhich solidifies on standing over a weekend. The crude product Weighs6.5 g. and recrystallization from n-heptane aifords cotton-like crystalsof 4-chloro-2-(3-chlorophenyl)-6-(4-methylpiperazin- 1-yl)-pyrim idine,M.P. 93-94 C.

Analysis-For C H N Cl Calcd.: C, 55.74%; H, 4.99%; N, 17.33%. Found: C,55.39%; H, 5.28%; N, 17.16%.

A well blended mixture of 4.25 g. of the above prepared pyrimidine and9.0 g. of p-chlorothiophenol is heated in an oil bath maintaining thetemperature at 160 C. for three hours. After being cooled to roomtemperature, the reaction mixture is triturated with 60 ml. of 30percent sodium hydroxide. The product is collected on a sintered glassfunnel and washed with water repeatedly. Recrystallization fromdimethylformamide affords 3.5 g. of 2-(3- chlorophenyl) 4 (4chlorophenylthio) 6 (4-methylpiperazin-l-yl)-pyrimidine, hydrochloride,M.P. 254-256" C. (dec.).

AnalySis.Fr CZ1HZQN4SCI3. Calcd.: C, H, 4.53%; N, 11.98%; S, 6.85%; Cl,22.74%. Found: C, 53.61%; H, 4.55%; N, 11.51%; S, 6.7%; Cl, 22.3%.

EXAMPLE XXI Repeating the procedure of Example XX, 7.2 g. of 4,6-dichloro-Z-(p-tolyl)-pyrimidine and 6.0 g. of N-methylpiperazine arereacted in 40 m1. of absolute ethanol. The crude product (8.4 g.) isseparated and twice recrystallized from n-heptane to aliord4-chloro-6-(4-methyl-1- piperazinyl)-2-(4-tolyl)-pyrimidine, M.P. 93-95C.

Analysis.-For C H N,Cl. Calcd.: C, 63.46%; H, 6.32%; N, 18.50%; Cl,11.71%. Found: C, 63.71%; H, 6.59 N, 18.56%; Cl, 11.5%.

The above prepared compound (4.5 g.) is then reacted with 9.0 g. ofp-chlorothiophenol for one hour. Recrystallization of the crude product(5.85 g.) from absolute ethanol with the addition of a few pellets ofpotassium hydroxide affords 4- (4-chlorophenylthio -6- (4-methy1-1-piperazinyl)-2-(4-tolyl)-pyrimidine, M.P. 103.5-105 C.

Analysis.For C H N SCl. Calcd.: C, 61.20%; H, 4.92%; N, 5.95%; S, 6.81%;Cl, 7.54%. Found: C, 60.84%; H, 4.74%; N, 6.15% S, 6.7%; Cl, 7.5%.

In a similar manner, the above prepared 4-ch1oro-6-(4-methyl-l-piperazinyl)-2-(4 tolyl) pyrimidine is reacted withp-ethoxythiophenol to afford 4-(4-ethoxypheny1thio)-6-(4-methyl-l-piperazinyl)-2-(4-tolyl)-pyrimidine.

EXAMPLE )QCII Employing the procedure of Example XX, 7.2 g. of4,6-dichloro-2-(4-tolyl)-pyrimidine is reacted With N-(B-aminoethyl)-morpholine to produce 7.7 g. of 4-chloro-6- [2- (morpholino)ethylamino] -2- (4-tolyl) -pyrimidine, M.P. 123-125 C.

Analysis-For C H N OCI. Calcd.: C, 61.34%; H, 6.36%; N, 16.84%; C1,10.65%. Found: C, 61.42%; H, 6.49%; N, 16.87%;Cl, 10.87%.

Reacting the above prepared pyrimidine (4.3 g.) with p-chlorothiophenol(9.0 g.), there is obtained 4-(4-chlorophenylthio) 6 (2morpholinoethylamino)-2-(4-tolyl) pyrimidine (6.9 g.), M.P. 141-142.5 C.

Analysis-For C H N SOCL Calcd.: C, 62.64%; H, 5.71%; N, 12.71%; S,7.27%; Cl, 8.04%. Found: C, 62.66%; H, 5.82%; N, 12.51%; S, 7.5%; Cl,8.2%.

EXAMPLE XXIII Employing the procedure of Example XX, 7.7 g. of4,6-dichloro-2-(4-methoxyphenyl)-pyrimidine is reacted with 6.0 g. ofN-methylpiperazine in 45 ml. of absolute ethanol to afford4-chloro-2-(4-metl1oxyphenyl-6-(4-methyl-l-piperazinyl)-pyrimidine, M.P.88-90 C.

Analysis-For C H N OCl. Calcd.: C, 60.28%; H, 6.01%; N, 17.58%; Cl,11.12%. Found: C, 60.19%; H, 6.07%; N, 17.86%; Cl, 11.2%.

Reacting the above prepared pyrimidine (5.8 g.) with p-chlorothiophenol(12 g.), there is obtained 4-(4-chlorophenylthio -2-(4 methoxyphenyl -6-(4-methylpiperazin- 1-yl)-pyrimidine (3.0 g.), M.P. 143-145 C.

Analysis.For C H N SOCL Calcd.: C, 61.88%; H, 5.43%; N, 13.12%; S,7.51%. Found: C, 61.64%; H, 5.33%;N, 12.91%; S, 7.5%.

In the same manner, the above prepared 4-chloro-2-(4- methoxyphenyl) -6-(4-methyl-1-piperazinyl -pyrimidine is reacted with p-propoxythiophenolto afford 2-(4-rnethoxyphenyD--(4-methyl-1-piperazinyl) -4- (4propoxyphenyithio}-pyrimidine.

EXAMPLE XXIV To 50 ml. of 20 percent ethanolic ethyl amine there isadded 10 g. of 4,6-dichloro-2-phenylpyrimidine. The reaction mixture isheated for 10 minutes on a steam-bath and evaporated to dryness in arotary evaporator in vacuo. Upon the addition of 175 ml. of water to theresidual oil, a crystalline product is deposited which amount to 10.8g., M.P. 62-65 C. Recrystallization from petroleum ether (B.P. 30-60C.)-n-pentane affords 6.7 g. of 4-chloro-6-ethylamino-Z-phenylpyrimidine, M.P. 65.5-67 C.

Analysis-For C H N Cl. Calcd.: C, 61.67%; H, 5.18%; N, 17.98%; Cl,15.17%. Found: C, 61.72%; H, 4.99%; N, 18.4%; C1, 14.8%.

A mixture of 0.7 g. of the above prepared 4-chloro-6-ethylamino-Z-phenylpyrimidine and 5 g. of p-chlorothiophenol is heatedto a temperature of 190 C. for three hours, then poured into 200 ml. ofwater after cooling. The aqueous mixture is basified with 10% sodiumhydroxide solution. The oily residue which deposits crystallizes oncooling to aiford 0.9 g. of material, M.P. -100 C. Recrystallizationfrom cyclohexane affords 0.4 g. of 4-(4- chlorophenylthio)-6-ethylamino-2-phenylpyrimidine, M.P. 109-110.5 C.

Analysis.-For C H N SCL Calcd.: C, 63.24%; H, 4.72%; N, 12.29; C1,10.37%; S, 9.38%. Found: C, 63.11%; H, 4.49%; N, 12.28%; Cl, 10.3%; S,9.5%.

In a similar manner, the following compounds are prepared:

6-methylamino-2-phenyl-4-phenylthiopyrimidine;

4-(4-bromophenylthio)-2-phenyl-6-propylaminopyrimidine; and

6-butylamino-2-(4-tolyl)-4-(4-toly1)thiopyrimidine.

EXAMPLE XXV A well blended mixture of 2.0 g.4-chloro-6-(4-methyll-piperazinyl)-2-phenylpyrimidine and 5.0 g. ofp-bromothiophenol is heated in an oil bath maintaining the temperatureat C. for three hours. After being cooled to room temperature, thereaction mixture is triturated with 60 m1. of 30% sodium hydroxide. Theproduct is collected on a sintered glass funnel and washed with waterrepeatedly. Upon recrystallization from absolute ethanol, there isobtained 4-(4-bromophenylthio)-6-(4methyl-1- piperazinyl-2-phenylpyrimidine.

Similarly, 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine isreacted with p-propylthiophenol to afford 6-(4-methyl-1-piperazinyl)-2-phenyl-4 (4 propylphenylthio)pyrimidine.

EXAMPLE XXVI A mixture of 6-amino-4-chloro-Z-phenylpyrimidine and 10 ml.of thiophenol is heated under reflux for three hours, then poured into300 ml. of water. The reaction mixture is basified with 40% sodiumhydroxide solution. The semisolid product which is depositedcrystallizes on coling to afford 6.9 g. of product. Recrystaliz'ation ofthis product from cyclohexane affords 4.5 g. of 4-amino-2-phenyl-6-phenylthiopyrirnidine, M.P. 109-111 C.

Analysis.-For C H N S. Calcd.: C, 68.79%; H, 4.69%; N, 15.04%; S,11.48%. Found: C, 69.00%; H, 4.44%; N, 14.77%; S, 11.2%.

Similarly, 5 g. of 4-amino-6-chloro-2-phenylpyrimidine is reacted with12 ml. of m-tolylthiophenol to aiford 2.6 g. of4-amino-2-phenyl-6-(3-tolylthio)-pyrimidine, M.P. 113-114.5 C.

Analysis.For C H N S. Calcd.: C, 69.59%; H, 5.15%; N, 14.32%; S, 10.93%.Found: C, 69.86%; H, 4.79%; N, 14.01%; S, 10.7%.

EXAMPLE XXVII A mixture of 5 g. of 4-amino-6-chloro-2-phenylpyrimidineand 15 ml. of 4-chlorobenzyl mercaptan is heated under reflux for 45minutes, then poured into 30 ml. of a 40% sodium hydrovide solution. Asolid separates which after recrystallization from cyclohexane gives 2.3g. of 4 amino 6-(4-chlorobenzylthio)-2-phenylpyrimidine, M.P. 138-1405C.

Analysis-For C H N SCl: Ca1cd.: C, 62.28%; H, 4.30%; N, 12.82%; Cl,10.81%; S, 9.78%. Found: C, 62.61%; H, 4.12%; N, 12.81%; Cl, 11.4%; S,10.0%.

In the above described maner, the following compounds are obtained:

4-amino-6-benzylthio-2-phenylpyrimidine;

4- (4-chlorobenzylthio -6- (2methoxyethylamino -2- (4-methoxyphenyD-pyrimidine;

2 (4 chlorophenyl) 4- (4-fluorobenzylthio) -6-[(2-dimethylaminoethyl)amino] pyrimidine;

4-amino-6- (4-bromobenzylthio -2-phenylpyrimidine;

3 4-methoxyphenyl) -4- (4-methylbenzylthio -6-[ (3-diethyl amino)propylamino -pyrimidine;

4-ethylamino-6- (4-methoxybenzylthio) -2-phenylpyrimidine;

4-amino-2-phenyl-6-(4-propoxybenzylthio) pyrimidine; and

4- (4-ethoxybenzylthio) -6- [2- (morpholinoethyl) amino]2-pheny1pyrimidine.

EXAMPLE XXVHI 6-chloro-4- [2-(dimethylamino)ethyl] amino-2phenylpyrimidine is obtained, as in Example VII, from 7.0 g. of4,6-dichloro-2-phenylpyrimidine and 30 m1. ofN,N-dimethylethylenediamine. The crude product thus obtained is mixedwith 15.0 g. of p-chlorothiophenol, and heated in an oil bathmaintaining the temperature at 160 C. for three hours. The reactionproduct is treated as in Example XXIV to give 8.3 g. of product, M.P.140-145 C. Recrystallization from 95% ethanol affords 4-(4chlorophenylthio) 6 -[(2-dimethylamino) ethylamino]-2-phenyl-pyrimidine, M.P. 147-149 C.

Analysis.For C H N SC1. Calcd.: C, 62.40%; H, 5.50%; N, 14.89%; S,8.33%. 'Found: C, 62.46%; H 5.21%; N, 14.91%; S, 8.5%.

Employing the above procedure, 7.0 g. of 4,6-dichloro-Z-phenylpyn'midine is reacted with 34 ml. of N,N-diethylethylenediamine,followed by the reaction of the crude product thereof with 12.5 g. ofp-chlorothiophenol. Recrystallization of the crude product (3.85 g.)from n-heptane affords 4-(4-chlorophenylthio)-6-[2-(diethy1-amino)ethylamino] 2 phenylpyrimidine, M.P. 83.5- 86 C.

Analysis.-Calcd for C H N.,SC1 (percent):

14 63.98; H, 6.10; N, 13.57; S, 7.76. Found (percent): C, 63.78; H,5.88; N, 13.65; S. 7.4.

EXAMPLE XXIX A mixture of 5.2 g. of4,6-dichloro-2-(M-chlorophenyl)-pyrimidine, 2.7 g. of aminoacetaldehydediethyl acetal and 20 ml. of ethanol is heated under reflux for one hourand then concentrated in vacuo on a rotary evaporator. The residualsolid is recrystallized from methanol affodding 4.5 g. of4-chloro-2-(3-chlorophenyl) 6 [(Z-diethoxyethyl)amino]-pyrimidine, M.P.99-101" C.

Analysis.Calcd for C H N SOC1 (percent): C, 53.94; H, 5.38; N, 11.80;Cl, 19.90. Found (percent): C, 54.08; H, 5.43; N, 12.11; Cl, 19.40.

The above prepared compound is then reacted with p-chlorothiophenol, asin Example XXIV, to produce 2 (3chlorophenyl)-4-(4-chlorophenylthio)-6-[(2-diethoxyethyl) amino]-pyrimidine In a similar manner,2-(4-chlorophenyl)-4-(4-methoxyphenylthio) 6[(2-dimethoxyethyl)amino]-pyrimidine is synthesized.

EXAMPLE XXX A mixture of 5.14 g. of 4-amino-6-chloro-2-phenylpyrimidineand 10.1 g. of p-chlorothiophenol is heated in an oil bath maintaining atemperature of C. for twenty minutes. The reaction mixture is trituratedwith hot 10% sodium hydroxide. The product is collected on a filter, andWashed with water repeatedly. The crude product weighs 8.0 g. and meltsat 118-121 C. Upon recrystallization from cyclohexane, there is obtained4 amino-6-(4-ch1oropheny1thio)Z-phenylptyrimidine, M.P. 124-125 C.

Analysis.Calcd for C H N SCl (percent): C, 61.24; H, 3.86; N, 13.39; S,10.22; Cl, 11.30. Found (percent): C, 60.96; H, 3.97; N, 13.66; S, 10.4;C1, 11.2.

What is claimed is:

1. A compound selected from the group consisting of those having theformula:

wherein R is selected from the group consisting of hydrogen, dichloro,halogen, loweralkyl and lower alkoxy; R isdi(lower)alkylamino(lower)alkylamino; and R is selected from the groupconsisting of phenyl and halophenyl.

2. A compound as described in claim 1 which is: 4- (4 chlorophenylthio)6-[(2-dimethylamino) ethyl] amino-Z-phenylpyrimidine.

3. A compound as described in claim 1 which is: 6-

.(4 chlorophenylthio) 4 [2-(diethylamino)ethyl] 7. A compound asdescribed in claim 1 which is: 4- (4 chlorophenyithio) 6[Z-(dimethylamino)ethylamino] -2- 4-to1yl -pyrimidine.

8. A compound as described in claim 1 which is: 4- (4 chlorophenylthio)2 (4-methoXypheny1)-6-[(2- dimethy1amin0)ethy1amin0]-pyrimidine.

9. A compound as described in claim 1 which is: 2- (3,4 dichlorophenyl)4 (4-chl0rophenyithio)-6-[2- (dimethyiamino )ethylamino] -pyrimidine.

1 6 References Cited Curd et 211.: Chemical Abstracts, vol. 42 (1948),pp.

U.S. Cl. X.R. 260247.1 424251

